Current vaccines induce the generation of B cells that secrete neutralizing antibodies targeting the influenza virus hemagglutinin (HA), but these antibody responses are quite strain-specific. However, several monoclonal antibodies have been described that exhibit relatively broad cross-neutralizing activity. In collaboration with Dr. James Crowe (Vanderbilt University), we recently described a human monoclonal antibody from a 1918 pandemic survivor which neutralized not only the 1918 virus but also human H1N1 viruses from 1943 and 1977. These data suggest that cross-reactive epitopes on different HA molecules exist;however, responses to such epitopes clearly do not predominate the human immune response to infection or vaccination. Our long term goal is to understand what determines the magnitude and specificity of human antibody responses to strain-specific versus broadly neutralizing HA epitopes, as this may facilitate development of more broadly protective vaccines. Toward this goal, we seek to characterize monoclonal antibodies from individuals born well after 1918 that neutralize the 1918 pandemic influenza virus. We other have separately detected high titer 1918-neutralizing antibodies in the sera of approximately 13 percent of individuals born well after 1918. Given that these individuals have not been exposed to the 1918 virus, the origin of these anti-1918 antibodies is unclear, but presumably they were elicited by exposure to other influenza virus strains. We hypothesize that some of these 1918-neutralzing antibodies will exhibit unusual cross-reactivity towards different H1 molecules. Therefore, we hope that defining the specificity of monoclonal 1918-neutralizing antibodies from these individuals will suggest strategies to elicit broad H1-neutralizing antibodies. We will (1) Develop efficient methods to isolate, from individuals born well after the 1918 influenza pandemic, 1918 hemagglutinin-specific human B cells and produce anti-1918 human monoclonal antibodies;and (2) Characterize 1918-specific human monoclonal antibodies from individuals born well after the 1918 influenza pandemic.. PUBLIC HEALTH RELEVANCE: Seasonal influenza continues to cause substantial morbidity and mortality annually in the United States, and the possible emergence of a new, pandemic influenza virus is a continuing concern. Completion of this project will identify the epitopes on the 1918 pandemic influenza virus HA recognized by antibodies from relatively young individuals. It is hoped this information will provide insight into new, more effective vaccine strategies.